Note: Descriptions are shown in the official language in which they were submitted.
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COMPOSITION AND METHOD FOR TREATING SEIZURE
DISORDERS
Ramachandra MUKUNDA
Ranga Chelva KRISHNA
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims priority on prior U.S.
Provisional Application S.N. 62/141,438, filed April 1, 2015, which is hereby
incorporated herein in its entirety by reference.
FIELD OF THE INVENTION
[0002] This invention relates to compositions and methods for
treating seizure disorders such as epilepsy in humans and animals
(mammals) using a non-barbiturate anti-epileptic drug (NAED),
phytocannabinoid cannabidiol (CBD); and a lipophilic fatty acid.
SUMMARY OF THE INVENTION
[0003] The invention provides compositions and methods for treating
seizure disorders such as epilepsy in humans and animals using, the
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combination of a non-barbiturate anti-epileptic drug (NAED),
phytocannabinoid cannabidiol (CBD); and a lipophilic fatty acid.
[0004] Patients who are subject to seizure disorders such as
epilepsy are treated to control and reduce the frequency of seizures by
administering the drug combination described above in accordance with
further details of the invention that are disclosed herein.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT(S)
OF THE INVENTION
[0005] Non-barbiturate anti-epileptic drugs (NAEDs) include:
[0006] acetozolamide
[0007] brivaracetam
[0008] carbamazepine
[0009] clobazam
[0010] clonazepam
[0011] ethosuximide
[0012] eslicarbazepine acetate
[0013] felbamate
[0014] flurofelbamate
[0015] gabapentin
[0016] lacosamide
[0017] lamotriquine
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[0018] levetriacetam
[0019] oxcarbazepine
[0020] perampanel
[0021] phenytoin
[0022] piracetam
[0023] pregabalin
[0024] primidone
[0025] rufinamide
[0026] seletracetam
[0027] sodium valproate
[0028] tiagabine
[0029] topiramate
[0030] valpro ate
[0031] vigabatrin
[0032] zonisamide
[0033] A preferred group of NAEDs bind to glyprotein SV2A and
includes levetriacetam (LEV) and derivatives or analogs thereof with anti-
epileptic drug activity such as brivaracetam (BVA) and seletracetam (SEA).
[0034] Preferred drugs such as Leveritacetam and analogs or
derivatives thereof bind to glycoprotein SV2A and act by modulating the
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release of calcium by inhibiting pre-synaptic calcium channels. This results
in reducing the release of excitatory neurotransmitters across the synaptic
cleft, thereby reducing the excitatory post-synaptic potential discharges.
[0035] The lipophilic fatty acid component increases the amount of
NAED and CBD crossing the blood brain barrier thereby increasing the
bioavailability of the NAED and CBD while decreasing or eliminating
undesirable side effects.
[0036] The preferred fatty acid is alpha linolenic acid ("ALA") or a
lipophilic mixture high in alpha linolenic acid. One such source is
hempseed oil extracted from the seed of the hemp plant (Cannabis Sativa).
Hempseed oil is essentially free of CBD and tetrahydrocannabinol (THC)
and is to be distinguished from hemp oil extracted from the glandular
structure of the hemp plant which contains CBD but not THC.
[0037] CBD can be used in its pure form or as a mixture of
compounds that result from extracting cannabis plants. Such mixtures
contain CBD, THC or tetrahydrocannabinol (which in turn is a mixture
comprising 9-tetrahydrocannabinol (delta-9 THC), 8-tetrahydrocannabinol
(delta-8 THC) and 9-THC Acid), Cannabinol (CBN), Cannabichromene
(CBC). Cannabigerol (CBG), terpenoids and flavonoids.
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[0038] The preferred CBD mixture is extracted from a Cannabis
Indica, the composition of which is known. The use of CBD from Cannabis
Indica, which can contain up to 50% THC (based on the amount of CBD), is
preferred. See, for example, Qureshi et al, World Applied Sciences Journal
19 (7): 918-923, 2012 ISSN 1818-4952, !DOS! Publications, 2012,
disclosing an lndicia extraction containing 54% CBD and 24% THC.
Preferred mixtures for use in the invention contain at least 50% by weight
CBD wherein the weight ratio of CBD to THC is at least 2:1, preferably at
least 3:1.
[0039] The preferred CBD mixture is extracted from a Cannabis
Indica dominant strain using high pressure and carbon dioxide as a solvent
in a 1500-20L subcriticalisupercritical CO2 system made by Apeks Super
Critical Systems, 14381 Blamer Rd., Johnstown, Ohio, 43031. See
http://www.apekssupercritical.com/botanical-extraction-systems/.
[0040] Apeks Systems use valveless expansion technology with no
constrictions or regulating valves to cause clogging in the system between
the extraction vessel and the CO2 expansion separator. Flow of liquid CO2
and dissolved oil travels from the extraction vessel into the separator, and
the oil is separated from the CO2 in the separator/collection vessel. CO2 is
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recycled during the extraction process and recovered and regenerative
heat capture methods are used to increase efficiency.
[0041] A further process using solvents can be used to remove THC
from the mixture leaving either pure CBD or so-called "Organic CBD"
containing CBD, CBN, CBC, CBG CBN, terpenoids and flavonoids. The
use of essentially THC-free Organic CBD from Cannabis Indica is more
preferred.
[0042] Another source of CBD essentially free of THC is the CBD
mixture obtained by extracting hemp oil from the glandular structure of the
hemp plant (Cannabis Sativa). See Leizer et al, J. Nutraceuticals,
Functional and Medical Foods, Vol. 2(4) 2000, The Haworth Press, Inc.
Hemp oil is to be distinguished from hempseed oil which contains neither
CBD nor THC.
[0043] NAEDs have been used to treat epilepsy and seizure
disorders. The addition of CBD creates an additional path to treat epilepsy
and or seizures wherein the overall impact of using the combination is
higher than those if treaded with each drug individually. Because the use
of a lipophilic fatty acid increases the amount of NAED and CBD crossing
the blood brain barrier which in turn increases the bioavailability of the
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NAED and CBD, lower dosage amounts of NAED can be used to
decreasing or eliminating undesirable side effects.
[0044] Patients
being treated for seizure disorders will receive a
NAED in an amount to provide from about 14 to about 40 micrograms of
said drug per milliliter of blood serum in a patient. To obtain these levels,
the daily dosage of a NAED will be about 4 mg/kg to 60mg/kg of patient
weight divided into two doses a day. For adults to neonates, the dosing will
be titrated to tolerability and efficacy not to exceed a total adult daily
dose
of about 6000 mg/day. The daily dosage amount of CBD to be used with a
NAED is from about 0.5 to about 1.0 mg/kg of patient weight. The daily
dosage of a fatty acid such as ALA will be about from 1 to 8 grams per day
depending on the body mass index of the patient.
[0045] Candidates to
be treated according to the invention will
generally present with symptoms or signs associated with seizure disorders
such as recurrent loss of consciousness, recurrent seizures and/or a prior
diagnoses of medically refractory epilepsy. The invention is especially
useful in treating patients who have had recurrent and/or poorly controlled
seizures or epilepsy in spite of being treated with one or more know
anticonvulsant drugs.
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[0046] The expected response in patients treated according to the
invention is a reduction in seizure intensity and/or frequency once a steady
state of the active pharmaceutical components is achieved. Up to 14 or
more days of treatment may be required before benefits can be achieved.
[0047] Patients with allergies, cardiac rhythm disturbances,
metabolic syndrome, renal failure, on dialysis, or with a history of Cannabis
abuse are not candidates to be treated according to the invention.
[0048] Animals, especially dogs and cats, can be treated according
to the invention. Seizures in dogs and cats are caused by abnormal brain
activity; they can be subtle or cause violent convulsions. Some seizures
only occur once but repeated seizures require treatment to prevent larger
areas of the brain from becoming affected. Dosage amounts and serum
levels of drug are the same as disclosed above for human patients.
[0049] While this invention has been described as having preferred
sequences, ranges, ratios, steps, order of steps, materials, structures,
symbols, indicia, graphics, color scheme(s), shapes. configurations,
features, components, or designs, it is understood that it is capable of
further modifications, uses and/or adaptations of the invention following in
general the principle of the invention, and including such departures from
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the present disclosure as those come within the known or customary
practice in the art to which the invention pertains, and as may be applied to
the central features hereinbefore set forth, and fall within the scope of the
invention and of the limits of the claims appended hereto or presented later.
The invention, therefore, is not limited to the preferred embodiment(s)
shown/described herein.
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